Despite the increasing body of knowledge and the growing development of specific therapies and diagnostic tools, colorectal cancer (CRC) remains the second leading cause of malignant mortality in industrialized nations, accounting for more than 13% of all cancer deaths (Remontet et al. Evolution de l'incidence de la mortalite par cancer 2003; www.insv.sante.fr, Cancer Incidence and Mortality Worldwide, Globocan 2008, WHO). The relative survival rates (ratio of observed survival over the expected survival in a group of people with the same gender and age) depend on the stage of CRC at diagnosis. Stage I tumours are associated with the highest relative survival rate, while those of stage 1V, known as poor prognosis (SEER 2006, O'Connell et al. 2004) with the lowest survival rate. Unfortunately, most cases of CRC are diagnosed in the already advanced stages when a curative surgical treatment is not possible, and chemotherapy remains the only option in spite of high costs and undesirable side effects. Because of the absence of efficient diagnostic methods of CRC, patients with colorectal neoplasia would most benefit from efficient early diagnostic CRC tests that can reveal early stages of CRC, thereby enabling preventive interventions.
The risk of CRC begins to increase after the age of 50; thereafter the risk continues to rise, approximately doubling with each succeeding decade (NCI-2006). Increased risk is slower in women and, before age 75, women have a lower incidence of CRC than men (Boyle P et al 2007). The desirable tests comprise as many as possible of the following features: average-risk, asymptomatic individuals, highly sensitive, non-invasive, low-risk, cost-effective, and ease of implementation across a large population. In many European countries, such as France, the Hemoccult gaiac test is currently recommended in screening campaigns as the first step: tests on three consecutive stool samples to detect occult blood. If the results are positive, this is followed by a second step: a colonoscopy to detect colorectal tumours. In the field of screening, blood tests are generally better accepted than faecal tests. However, no formal seric test is currently available for CRC. The development of the first assays of serum carcinoembryonic antigen (CEA) in 1965 raised considerable hope on the possibility of screening test in blood (Gold et al 1965, Thompson et al 1969). However, subsequent work showed that the sensitivity of CEA was less than 35% in individuals with invasive cancer; it could not detect early forms and its specificity was insufficient, since its serum levels increase in several pathologies. The limitations of the CA19-9 antigen, introduced more recently (Ritts 1984), are comparable to those of CEA. The current use of these two molecules is limited to post-therapeutic surveillance.
DNA methylation plays a substantial role in colorectal cancer (CRC) development. It induces a change of transcriptome profile in epithelial colon cells. The down-regulation of some genes is induced by the methylation mechanism of CpG islands in their promoters, which inhibits the ability of transcription factors to induce the expression of the target genes. In addition to the role of the involvement of methylation mechanism in the genomic instability of colon epithelial cells during the CRC development, the methylation pattern of some genes is useful to screen and detect patients having different stages of CRC. A convenience is that such methylation tests can be done using body fluids, such as serum and others. The present invention satisfies a need in the art to provide biomarkers for colorectal cancer screening that are highly sensitive and specific.